HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites

The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.     

The methodological origins of Newton’s queries

This paper analyses the different ways in which Isaac Newton employed queries in his writings on natural philosophy. It is argued that queries were used in three different ways by Newton and that each of these uses is best understood against the background of the role that queries played in the Baconian method that was adopted by the leading experimenters of the early Royal Society. After a discussion of the role of queries in Francis Bacon’s natural historical method, Newton’s queries in his Trinity Notebook are shown to reveal the influence of his early reading in the new experimental philosophy. Then after a discussion of Robert Hooke’s view of the role of queries, the paper turns to an assessment of Newton’s correspondence and Opticks. It is argued that the queries in his correspondence with Oldenburg on his early optical experiments are closely tied to an experimental program, whereas the queries in the Opticks are more discursive and speculative, but that each of these uses of queries represents a significant Baconian legacy in his natural philosophical methodology.     

Aggregation of equivalence relations

Each ofn attributes partitions a set of items into equivalence classes. Aconsistent aggregator of then partitions is defined as an aggregate partition that satisfies an independence condition and a unanimity condition. It is shown that the class of consistent aggregators is precisely the class ofconjunctive aggregators. That is, for each consistent aggregator there is a nonempty subsetN of the attributes such that two items are equivalent in the aggregate partition if and only if they are equivalent with respect to each attribute inN.     

The Ackoff factor

My mother wanted me to become a wealthy corporate executive. My father didn't care what I became as long as I didn't do too well at it. Russ Ackoff wanted me to become whatever I wanted, and the better I could do at it, the happier he would be. I chose the last of these and have enjoyed every minute. Thanks, Russ.     

The consistency,coherence and calibration of holistic,decomposed and recomposed judgemental probability forecasts

In this paper we make an empirical investigation of the relationship between the consistency, coherence and validity of probability judgements in a real-world forecasting context. Our results indicate that these measures of the adequacy of an individual's probability assessments are not closely related as we anticipated. Twenty-nine of our thirty-six subjects were better calibrated in point probabilities than in odds and our subjects were, in general more coherent using point probabilities than odds forecasts. Contrary to our expectations we found very little difference in forecasting response and performance between simple and compound holistic forecasts. This result is evidence against the ‘divide-and-conquer’ rationale underlying most applications of normative decision theory. In addition, our recompositions of marginal and conditional assessments into compound forecasts were no better calibrated or resolved than their holistic counterparts. These findings convey two implications for forecasting. First, untrained judgemental forecasters should use point probabilities in preference to odds. Second, judgemental forecasts of complex compound probabilities may be as well assessed holistically as they are using methods of decomposition and recomposition. In addition, our study provides a paradigm for further studies of the relationship between consistency, coherence and validity in judgemental probability forecasting.     

Seasonal adjustment and kalman filtering: Extension to periodic variances

This paper reviews the relations between the methods of seasonal adjustment used by official statistical agencies and the ‘model-based’ methods that postulate explicit stochastic models for the unobserved components of a time series and apply optimal signal extraction theory to obtain a seasonally adjusted series. The Kalman filter implementation of the model-based methods is described and some recent results on its properties are reviewed. The model-based methods employ homogeneous or time-invariant models that assume in particular that the autocovariance structure does not vary with the season. Relaxing this leads to the class of models known as periodic models, and an example of a seasonally heterosceclastic unobserved-components ARIMA (SHUCARIMA) model is presented. The calculation of the standard error of a seasonally adjusted series via the Kalman filter is extended to this periodic model and illustrated for a monthly rainfall series.     

Dissociation between compensatory renal growth and induction of (Na++K+-ATPase in rat kidney after uninefrectomy

Zusammenfassung Nach Uninephrektomie und bilateraler Adrenalektomie entsteht eine Dissoziation zwischen der Nierenvergrösserung und der (Na⁺+K⁺)-ATPase Aktivität. Es besteht wahrscheinlich kein Zusammenhang zwischen der Nierenvergrösserung und der Induktion von (Na⁺+K⁺)-ATPase. Auch in der vergrösserten Niere sind die Nebennierenhormone notwendig, um die (Na⁺+K⁺)-ATPase zu erhalten.

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The work was supported by a grant from P. Carl Petersen's Fund. Mrs.Birthe Bagge Hansen provided excellent technical assistance.